The proposed research continues studies which were designed to elucidate the relationship between the acute and chronic behavioral effects of d-lysergic acid diethylamide (LSD) and the activity of brain monoamines, serotonin (5-HT) and norepinephrine (NE). More specifically, four questions grew out of our finding that pretreatment with reserpine and p-chlorophenylalanine (PCPA), both of which lower the concentration of 5-HT in brain, enhance the disruptive effect of low doses of LSD on behavior maintained under a simple schedule of (positive) reinforcement (Fixed-ratio or FR). 1) Is hypersensitivity to LSD related to the physiological or biochemical activities of serotonergic neuronal systems or to some other effect of pretreatment agents? 2) Is hypersensitivity reversible, can it be altered by manipulating amine concentrations or mechanisms? 3) Are other, more chronic behavioral effects of hallucinogens similarly affected by altered amine availability? 4) What is the generality of the relationship between hallucinogenic drug effects and amine metabolism? Each of these questions will be investigated biochemically and in two behavioral situations involving a) the measurement of the disruptive effects of hallucinogens on fixed-ratio performance after pretreatment, and b) the assessment of ability to discriminate (sense) the presence or absence of test drugs (state-dependent or dissociated learning).